PDF(Pubmed)
Abstract：
UNASSIGNED: ANG (angiotensin II) elicits dipsogenic and pressor responses via activation of the canonical Gαq (G-protein component of the AT1R [angiotensin type 1 receptor])-mediated AT1R in the subfornical organ. Recently, we demonstrated that ARRB2 (β-arrestin 2) global knockout mice exhibit a higher preference for salt and exacerbated pressor response to deoxycorticosterone acetate salt. However, whether ARRB2 within selective neuroanatomical nuclei alters physiological responses to ANG is unknown. Therefore, we hypothesized that ARRB2, specifically in the subfornical organ, counterbalances maladaptive dipsogenic and pressor responses to the canonical AT1R signaling.
UNASSIGNED: Male and female Arrb2FLOX mice received intracerebroventricular injection of either adeno-associated virus (AAV)-Cre-GFP (green fluorescent protein) to induce brain-specific deletion of ARRB2 (Arrb2ICV-Cre). Arrb2FLOX mice receiving ICV-AAV-GFP were used as control (Arrb2ICV-Control). Infection with ICV-AAV-Cre primarily targeted the subfornical organ with few off targets. Fluid intake was evaluated using the 2-bottle choice paradigm with 1 bottle containing water and 1 containing 0.15 mol/L NaCl.
UNASSIGNED: Arrb2ICV-Cre mice exhibited a greater pressor response to acute ICV-ANG infusion. At baseline conditions, Arrb2ICV-Cre mice exhibited a significant increase in saline intake compared with controls, resulting in a saline preference. Furthermore, when mice were subjected to water-deprived or sodium-depleted conditions, which would naturally increase endogenous ANG levels, Arrb2ICV-Cre mice exhibited elevated saline intake.
UNASSIGNED: Overall, these data indicate that ARRB2 in selective cardiovascular nuclei in the brain, including the subfornical organ, counterbalances canonical AT1R responses to both exogenous and endogenous ANG. Stimulation of the AT1R/ARRB axis in the brain may represent a novel strategy to treat hypertension.
UNASSIGNED: Male and female Arrb2FLOX mice received intracerebroventricular injection of either adeno-associated virus (AAV)-Cre-GFP (green fluorescent protein) to induce brain-specific deletion of ARRB2 (Arrb2ICV-Cre). Arrb2FLOX mice receiving ICV-AAV-GFP were used as control (Arrb2ICV-Control). Infection with ICV-AAV-Cre primarily targeted the subfornical organ with few off targets. Fluid intake was evaluated using the 2-bottle choice paradigm with 1 bottle containing water and 1 containing 0.15 mol/L NaCl.
UNASSIGNED: Arrb2ICV-Cre mice exhibited a greater pressor response to acute ICV-ANG infusion. At baseline conditions, Arrb2ICV-Cre mice exhibited a significant increase in saline intake compared with controls, resulting in a saline preference. Furthermore, when mice were subjected to water-deprived or sodium-depleted conditions, which would naturally increase endogenous ANG levels, Arrb2ICV-Cre mice exhibited elevated saline intake.
UNASSIGNED: Overall, these data indicate that ARRB2 in selective cardiovascular nuclei in the brain, including the subfornical organ, counterbalances canonical AT1R responses to both exogenous and endogenous ANG. Stimulation of the AT1R/ARRB axis in the brain may represent a novel strategy to treat hypertension.
摘要：
■ANG（血管紧张素II）通过激活规范的Gαq（AT1R[血管紧张素1型受体]的G蛋白成分）介导的AT1R引起双源和升压反应。最近,我们证明ARRB2(β-抑制蛋白2)基因敲除小鼠对盐的偏好更高,对脱氧皮质酮乙酸盐的升压反应加剧.然而,选择性神经解剖核内的ARRB2是否改变对ANG的生理反应尚不清楚。因此,我们假设ARRB2，特别是在穹窿下器官，平衡了对典型AT1R信号传导的适应不良的同系和升压反应。
■雄性和雌性Arrb2FLOX小鼠接受脑室内注射腺相关病毒（AAV）-Cre-GFP（绿色荧光蛋白）以诱导ARRB2的脑特异性缺失（Arrb2ICV-Cre）。将接受ICV-AAV-GFP的Arrb2FLOX小鼠用作对照(Arrb2ICV-对照)。ICV-AAV-Cre的感染主要靶向穹窿下器官，很少脱靶。使用2瓶选择范例评估流体摄入量，其中1瓶含有水，1瓶含有0.15mol/LNaCl。
■Arrb2ICV-Cre小鼠对急性ICV-ANG输注表现出更大的升压反应。在基线条件下，与对照组相比，Arrb2ICV-Cre小鼠的盐水摄入量显着增加，导致盐水偏好。此外，当小鼠受到缺水或贫钠的条件时，这自然会增加内源性ANG水平，Arrb2ICV-Cre小鼠表现出盐水摄入量升高。
■总的来说，这些数据表明，ARRB2在大脑中的选择性心血管核中，包括穹窿下的器官,平衡了典型的AT1R对外源和内源ANG的反应。刺激大脑中的AT1R/ARRB轴可能代表了治疗高血压的新策略。
■雄性和雌性Arrb2FLOX小鼠接受脑室内注射腺相关病毒（AAV）-Cre-GFP（绿色荧光蛋白）以诱导ARRB2的脑特异性缺失（Arrb2ICV-Cre）。将接受ICV-AAV-GFP的Arrb2FLOX小鼠用作对照(Arrb2ICV-对照)。ICV-AAV-Cre的感染主要靶向穹窿下器官，很少脱靶。使用2瓶选择范例评估流体摄入量，其中1瓶含有水，1瓶含有0.15mol/LNaCl。
■Arrb2ICV-Cre小鼠对急性ICV-ANG输注表现出更大的升压反应。在基线条件下，与对照组相比，Arrb2ICV-Cre小鼠的盐水摄入量显着增加，导致盐水偏好。此外，当小鼠受到缺水或贫钠的条件时，这自然会增加内源性ANG水平，Arrb2ICV-Cre小鼠表现出盐水摄入量升高。
■总的来说，这些数据表明，ARRB2在大脑中的选择性心血管核中，包括穹窿下的器官,平衡了典型的AT1R对外源和内源ANG的反应。刺激大脑中的AT1R/ARRB轴可能代表了治疗高血压的新策略。
